DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Priority to 63/021,179, filed 5/7/2020, is acknowledged.
Claim Status
Claims 5-16, 19-20, 22, 26-29, 32, 34-35, 38, and 40-45 are currently pending. Claims 5-16, 19-20, 22, 26-29, 32, 34-35, 38, and 40-45 are under examination. Claims 25 and 33 are canceled.
Claim Interpretation
Claims 34, 35, and 38 recite a list of elements with the last element listed following “and/or”. This can be interpreted as the “and/or” applies to each element or only the last element.
For purposes of examination, the broadest reasonable interpretation is that the entire list of elements is construed in the alternative.
Previous Claim Objections
Claims 5, 6, 7, and 10 were previously objected to because each contains redundant and superfluous language that fails to meaningfully limit the pending claim scope.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 9, para. 8, filed 5/28/2026, with respect to claims 5, 6, 7, and 10 have been fully considered and are persuasive. The objection to claims 5, 6, 7, and 10 has been withdrawn.
New Claim Objections
Claims 40-43 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Previous Claim Rejections - 35 USC § 101
Claims 5, 8, and 15 were previously rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon without significantly more.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 9, para. 9, filed 5/28/2026, with respect to claims 5, 8, and 15 have been fully considered and are persuasive. The rejection of claims 5, 8, and 15 has been withdrawn.
Previous Claim Rejections - 35 USC § 112
Claims 19, 20, 22, 25- 29, 32, and 33 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Claims 25 and 33 have been canceled, rendering the rejection moot.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 1, filed 5/28/2026, with respect to claims 19, 20, 22, 26- 29, 32, and 33 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made below.
New Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5-16, 34-35, 38, and 44-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claim 5 recites an isolated nucleic acid that encodes a mutant SIRT5 protein at least 90% identical to SEQ ID NO: 4 or SEQ ID NO: 10, wherein the protein retains arginine at one or more positions 79, 112, 148, 152 of SEQ ID NO: 4 or SEQ ID NO: 10. This amended claim still encompasses an enormous sequence space. As an approximation, the protein encoded is 310 amino acids in length. Allowing 10% variance gives 31 possible mutations. Removing a required arginine residue leaves 30 possible mutations Ignoring position of mutations, this yields 20^30 possible proteins. The nucleic acid sequences encoding these proteins are degenerate, but would still be within a few factors of 20^30. Without possessing a representative number of examples of the protein genus, the nucleic acid genus also cannot be possessed.
In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As described above, claim 5, and therefore claim 19, recites extremely large genus of nucleic acids.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
In the instant case, Applicant reduces two sequences to practice: SEQ ID NO: 4 and SEQ ID NO: 10. These are a tiny fraction of the sequences encompassed by the current claim breadth.
At the time the invention was made, the level of skill for preparing peptides (and encoding nucleic acids) with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide (and encoding nucleic acids) with a particular set of properties, in this case, SIRT5 activity, would look like structurally. Therefore, the provided examples only represent a limited structural diversity.
Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every peptide molecule recited by claim 5. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claim 5 is rejected.
Regarding claim 6, claim 5 is rejected as described above. Claim 6 further recites the case wherein the nucleic acid of claim 5 comprises a sequence with 80% identity to SEQ ID NO: 3 or SEQ ID NO: 9, which encodes SEQ ID NO: 4 and SEQ ID NO: 10 respectively.
This claim does not reduce the genus size of the claimed nucleic acid of claim 5 from an amino acid perspective. Additionally, this also recites the case wherein 930 * 0.2 = 186 possible nucleic acid substitutions, removing 4 for the required arginine codon, this leaves 182 possible substitutions, yielding at least 4^182 possible resulting nucleic acids. Degeneracy is present, but the resultant genus is still enormous. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claim 6 is rejected.
Regarding claim 7, claim 5 is rejected as described above. Claim 6 further recites the case wherein the nucleic acid of claim 5 comprises a sequence with 80% identity to SEQ ID NO: 3 or SEQ ID NO: 9, which encodes SEQ ID NO: 4 and SEQ ID NO: 10 respectively.
This claim does not reduce the genus size of the claimed nucleic acid of claim 5 from an amino acid perspective. Additionally, this also recites the case wherein 930 * 0.2 = 186 possible nucleic acid substitutions, removing 12 for the required arginine codons, this leaves 174 possible substitutions, yielding at least 4^174 possible resulting nucleic acids. Degeneracy is present, but the resultant genus is still enormous. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus
Consequently, claim 7 is rejected.
Regarding claims 8 and 9, claim 5 is rejected as described above.
Regarding claim 10, claim 9 is rejected as described above. This claim does not reduce the genus size of claim 9. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claim 10 is rejected.
Regarding claims 11-16, claim 9 is rejected as described above. These claims do not reduce the genus size of claim 9. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claims 11-16 are rejected.
Regarding claims 34, 35, 38, claim 5 is rejected as described above. These claims do not reduce the genus size of claim 5. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claims 34, 35, and 38 are rejected.
Regarding claim 44, claim 5 is rejected as described above. Claim 44 reduces the genus size to around 20^14 peptides, but this is still enormous. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claim 44 is rejected.
Regarding claim 45, claim 6 is rejected as described above. Claim 45 reduces the genus size to around 4^91 nucleic acids, but this is still enormous. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Consequently, claim 45 is rejected.
Examiner note: Claim 40 is not rejected because it sufficiently reduces the genus size claimed.
Previous Claim Rejections - 35 USC § 112
Claims 19, 20, 25-29, 32, and 33 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of an organic acidemia that results in the methylmalonylation or malonylation, a vitamin B12 deficiency, or a metabolic disorder that results in the methylmalonylation or malonylation with the proteins encoded by SEQ ID NO: 4 and SEQ ID NO: 10, does not reasonably provide enablement for the treatment of any possible metabolic disorder with the full range of proteins encoded by the claimed nucleic acids of claim 5.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 1, filed 5/28/2026, with respect to claims 19, 20, 22, 26- 29, 32, and 33 have been fully considered and are persuasive. The rejection of claims 19, 20, 22, 26- 29, and 32 have been withdrawn.
Claim 22 was previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing PTMs in a subject having an organic acidemia that results in the methylmalonylation or malonylation, a vitamin B12 deficiency, a metabolic disorder that results in the methylmalonylation or malonylation, or reducing blood ammonia by at least 10% in a subject having an organic acidemia that results in the methylmalonylation or malonylation with the proteins encoded by SEQ ID NO: 4 and SEQ ID NO: 10, does not reasonably provide enablement for reducing PTMs or caused by any possible metabolic disorder with the full range of proteins encoded by the claimed nucleic acids of claim 5, or reducing blood ammonia by at least 10% in a subject with any possible organic acidemia.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 1, filed 5/28/2026, with respect to claim 22 have been fully considered and are persuasive. The rejection of claim 22 has been withdrawn.
Claim Rejections - 35 USC § 102
Claims 34, 35, and 38 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gerbanowski e et al. (Gerbanowski, A., et al. Journal of protein chemistry 18.3: 325-336 (1999)).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 4, filed 5/28/2026, with respect to claims 34, 35, and 38 have been fully considered and are persuasive. The rejection of claims 34, 35, and 38 has been withdrawn.
Claim Rejections - 35 USC § 103
Claims 5, 8, 9, 13, 14 were previously rejected under 35 U.S.C. 103 as being unpatentable over UniProt entry A0A2Y9P5P3, published 9/12/2018, accessed 3/2/2026 over Codon Usage Database, https://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=4932, published 6/15/2007, accessed 3/2/2026 and Hartley et al. (Hartley, James L. Current Opinion in Biotechnology 17.4: 359-366 (2006)).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 4, filed 5/28/2026, with respect to claims 5, 8, 9, 13, and 14 have been fully considered and are persuasive. The rejection of claims 5, 8, 9, 13, and 14 has been withdrawn.
Claims Free of the Prior Art
Amended claim 5 is now free of the prior art. The polypeptide encoded by the nucleic acid of claim 5 is not taught or suggested by the prior art. No prior art that meets the required arginine substitution has 90% identity to Applicant SEQ ID NO: 4 or Applicant SEQ ID NO: 10.
The closest available prior art is Uniprot Accession No: A0A2Y9P5P3 is aligned against Applicant SEQ ID NO: 4 below:
# Aligned_sequences: 2
# 1: EMBOSS_001
# 2: EMBOSS_001
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 310
# Identity: 275/310 (88.7%)
# Similarity: 288/310 (92.9%)
# Gaps: 0/310 ( 0.0%)
# Score: 1465.0
#
#
#=======================================
EMBOSS_001 1 MPPLRIVPSRLLSQLYCGLKPPASIQTKICLTMARPSSSMADFRKCFAKA 50
|.||:||||||:||||||||||||.:.:|||.|||||||||||||.||||
EMBOSS_001 1 MRPLQIVPSRLISQLYCGLKPPASTRNQICLKMARPSSSMADFRKFFAKA 50
EMBOSS_001 51 KHIVIISGAGVSAESGVPTFRGAGGYWRRWKAQDLATPQAFARNPSQVWE 100
||||||||||||||||||||||||||||||:|||||||.|||.|||:|||
EMBOSS_001 51 KHIVIISGAGVSAESGVPTFRGAGGYWRRWQAQDLATPLAFAHNPSRVWE 100
EMBOSS_001 101 FYHYRREVVQSKEPNAGHLAIA ECEARLGRQGRRVTVITQNIDELHRKAG 150
||||||||:.|:||||||.||||||.|||:|||||.|||||||||||:||
EMBOSS_001 101 FYHYRREVMGSREPNAGHRAIA ECETRLGKQGRRVVVITQNIDELHRRAG 150
EMBOSS_001 151 TKNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPETQDARIP 200
|:||||||||||||||||||||||||||||||||||||||||.||||.||
EMBOSS_001 151 TRNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPGTQDASIP 200
EMBOSS_001 201 VEKLPRCEEAACGGLLRPHVVWFGENLDPAILEEAGRELALCDLCLVVGT 250
||||||||||.|||||||||||||||||||||||..||||.|||||||||
EMBOSS_001 201 VEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELAHCDLCLVVGT 250
EMBOSS_001 251 SSVVYPAAMFAPEVSARGVPVAEFNIEATPAANRFRFHFQGPCGTTLPEA 300
||||||||||||:|:||||||||||.|.|||.||||||||||||||||||
EMBOSS_001 251 SSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEA 300
EMBOSS_001 301 LAPHETETVS 310
||.||.||||
EMBOSS_001 301 LACHENETVS 310
This sequence has 88.7% identity with Applicant SEQ ID NO: 4, and position 79 is an arginine. However, amended claim 5 requires 90% sequence identity.
Regarding claim 6, claim 5 is free of the prior art so claim 6 is also necessarily free of the prior art.
Regarding claim 7, no prior art possesses the required quadruple arginine substation.
Consequently, claim 7 is free of the prior art.
The same reasoning applies to claims 8-16, 34-35, 38, and 44-45.
Allowable Subject Matter
Amended claims 19, 20, 22, 26-29, and 32 are allowable. Specifically, claim 19 does not reference any of the claims rejected under U.S.C. 112(a). Claim 19 has full written description support and enablement after amendment. The same logic applies to 20, 22, 26-29 and 32.
Claims 40-43 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. These claims were previously indicated as allowable, but require the base claim to be placed in condition for allowance or be rewritten as independent claims. The status of these claims is properly updated in this office action.
Conclusion
Claims 19, 20, 22, 26-29, and 32 are allowable.
Claims 5-16, 34-35, 38, and 44-45 are rejected.
Claims 40-43 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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